Original Article

Journal of Child Neurology

2020, Vol. 35(1) 37-41
A Single Institution’s Experience of Primary ª The Author(s) 2019
Article reuse guidelines:
sagepub.com/journals-permissions
Headache in Children With Celiac Disease DOI: 10.1177/0883073819873751
journals.sagepub.com/home/jcn

Grant L. Hom, BA1,2 , Brian L. Hom, MD2,3, Barbara Kaplan, MD4,

and A. David Rothner, MD2

Abstract
Background: Few studies exist examining the frequency of primary headache in children with celiac disease and the impact of a
gluten-free diet on primary headache symptomology. This study explores characteristics and frequency of headaches in children
with celiac disease and response to gluten-free diet at a single institution. Methods: Medical records were reviewed for children
with celiac disease confirmed by the presence of elevated tissue transglutaminase IgA levels and histologic changes consistent with
the diagnosis of celiac disease on small bowel biopsy. Eligible participants were contacted via letter for participation in a phone
survey regarding headaches. Phone interviews were conducted 2 weeks after notification and lasted approximately 10 minutes.
Headaches were classified according to ICHD-3 criteria. Results: 247 eligible patients or their families were contacted. A total of
132 (53.44%) agreed to participate. One participant was excluded due to insufficient information provided. Overall, 51 of 131
participants had recurrent headache defined as at least 1 episode per month (39%, 95% confidence interval [CI]: 31%-47%) and 33
had migraine with or without aura (25%, 95% CI: 18%-33%). Twenty-eight had frequent tension-type headache (22%, 95% CI: 15%-
29%). Thirty-two participants noted headaches before a confirmed diagnosis of celiac disease. Twenty-two of 32 participants
(68.75%) noticed decreased headache frequency or intensity, or both, after starting the gluten-free diet. Conclusion: This study
suggests that at least one-third of children and adolescents with celiac disease have recurrent headaches at the time of diagnosis. A
gluten-free diet led to improved headache symptomology in a significant number of these patients.

Keywords
primary headache, celiac disease, migraine, questionnaire, children

Received May 23, 2019. Received revised July 5, 2019. Accepted for publication August 8, 2019.

Celiac disease is an autoimmune enteropathy triggered by
dietary-gluten consumption and appears in genetically predis-
posed individuals with human leukocyte antigen haplotypes
DQ2 and DQ8.1 Gluten is a protein found in wheat, rye, and
barely. Celiac disease appears in about 1% of children and
adolescents in the United States. Celiac disease symptoms vary
widely from patient to patient. Classical symptoms of celiac
disease in children appear weeks to months after exposure to
gluten and include diarrhea, vomiting, nonspecific abdominal
pain, failure to thrive, weight loss, and short stature. Over the
past decade, these classical symptoms of celiac disease are less
commonly seen in children, with the most common presenta-
tion being nonspecific abdominal pain. Celiac disease is also
frequently diagnosed in asymptomatic children who are iden-
tified through recommended celiac disease screening after a
family member has been diagnosed with celiac disease. In
addition, there are also numerous recognized extraintestinal
symptoms described in children with celiac disease, including
fatigue, headache, delayed puberty, elevated liver enzymes,
and dermatitis herpetiformis. These symptoms can be quite
variable and may appear at any age.
Previous studies support an association between celiac dis-
ease and neurologic disorders such as developmental delay,
learning disorders, attention-deficit/hyperactivity disorder
(ADHD), cerebellar ataxia, and headache.2,3 Several studies
have confirmed headache as a common manifestation in celiac
disease patients.4-7 Lebwohl et al4 in a population-based study
reported increased headache-related health care visits in
patients with celiac disease compared to controls (4.7% vs
2.9%). Migraine has been the primary headache of interest in
studying associations with celiac disease. In another study,
1
Case Western Reserve University, Cleveland, OH, USA
2
Cleveland Clinic Department of Pediatric Neurology, Cleveland, OH, USA
3
Northeast Ohio Medical University, Rootstown, OH, USA
4
Cleveland Clinic Department of Pediatric Gastroenterology, Cleveland, OH,
USA
Corresponding Author:
A. David Rothner, MD, Department of Pediatric Neurology, The Cleveland
Clinic Foundation, 9500 Euclid Avenue S60, Cleveland OH, 44195, USA.
Email: rothned@ccf.org
38 Journal of Child Neurology 35(1)

Dimitrova and colleagues8 showed that 21% of their adult Table 1. Study Participant Demographics and Overall Headache
celiac disease cohort had migraine whereas 30% had chronic Results (N¼131).
headaches, which were higher in frequency than in the control Factor n Statisticsa
group. Nenna and colleagues9 determined an increased fre-
quency of celiac disease (2%) in their recurrent headache sam- Age when data collected, y 131 11.6 + 3.4
ple compared to control (1%). In the study by Alehan and Gender 131
colleagues,10 5.5% of migraine patients had positive celiac Female 79 (60.3)
Male 52 (39.7)
disease blood tests whereas only 0.6% of control patients had Age of CD onset, y 123 5.4 + 4.1
positive celiac disease blood tests. Gabrielli et al11 also saw a Age of CD diagnosis, y 131 7.4 + 4.0
higher celiac disease frequency in the migraine sample (4.4%) Time on gluten-free diet, y 131 4.3 + 3.6
compared to controls (0.4%) based on serum test and endo- Compliance to gluten-free diet 131
scopy. In contrast, Inaloo et al12 reported that there was no Strict 119 (90.8)
difference between the frequency of celiac disease in the Moderate 11 (8.4)
Loosely 1 (0.76)
migraine population and the control population.
CD in family 131 53 (40.5)
The goal of this study is to add to the expanding literature HA in family 131 88 (67.2)
on this topic with a focus on primary recurrent headaches in Type of HA seen in family 88
children and adolescents and the effects of a gluten-free diet Migraine 60 (68.2)
on headache improvement. Thus, our study aims were (1) to Tension type 17 (19.3)
determine the frequency of recurrent primary headaches in Migraine þ chronic tension type 4 (4.5)
Cluster HA 2 (2.3)
a population of children and adolescents with celiac disease
Migraine þ cluster HA 1 (1.2)
at a single institution; (2) to determine whether adherence Unclassified 4 (4.5)
to a gluten-free diet reduces the frequency and severity of Learning disorder history 131 8 (6.1)
the headaches. Attention-deficit disorder history 131 12 (9.2)
Balance problems history 131 4 (3.1)
Felt tingling history 131 13 (9.9)
Felt weakness history 131 12 (9.2)
Methods Seizures currently 131 0 (0.0)
Seizures past 131 2 (1.5)
Data were collected from August 2014 to June 2017. We performed a
Seizures with fever 131 1 (0.76)
retrospective chart review to identify patients who were diagnosed
Developmental disorder history 131 2 (1.5)
with celiac disease as children (5-17 years) via both positive duodenal Any headache 131
biopsies and elevated tissue transglutaminase IgA titers. A total of 252 No headaches 80 (61.1)
pediatric celiac disease patients from a single institution’s medical Headaches 51 (38.9)
records qualified for this study. Exclusion criteria include patients Child’s headaches 131
who were developmentally delayed unless information could be No HA 80 (61.1)
obtained from parents and those with a medical history that could Migraine 22 (16.8)
contribute to headache (eg, head trauma, brain tumor, chronic neck Frequent episodic tension type 9 (6.9)
pain, neck injury, uncorrected vision problems). All patients were Chronic tension type 8 (6.1)
notified of the study via mail. Follow-up phone interviews took place Migraine episodic tension-type HA 6 (4.6)
2 to 4 weeks after letters were sent and generally lasted about 10 Migraine þ chronic tension-type HA 5 (3.8)
minutes. Questions were standardized based on questions used at a Cluster HA 1 (0.76)
single institution’s pediatric/adolescent headache clinic (Appendix 1).
Abbreviations: CD, celiac disease; HA, headache.
Study participants’ history of celiac disease, neurologic history, and a
Statistics presented as mean + SD, or n (column %).
family history of celiac disease and headache were collected. Head-
aches were classified according to ICHD-3 criteria. Possible partici-
pants were contacted up to three times. Generally, questions were Results
answered by the parent only for children aged 5-8 years, by both the Of the 247 contacted patients, 132 agreed to participate. Eleven
parent and child for children aged 9-12 years, and with the child only were unreachable determined by returned mail or disconnected
for age 13-18 years after obtaining parent consent. This study was phone numbers, and 104 either declined participation or did not
approved by the Cleveland Clinic Foundation’s Institutional Review return phone calls. Study response rate was 53.44%. Data from
Board.
1 study participant were removed from our sample analysis
Data analysis was performed using SAS, version 9.3 (SAS Institute
owing to insufficient information. The mean age of this sample
Inc, Cary, NC). Descriptive statistics were used to characterize our
sample. Qualitative variables were expressed as frequency, and quan- (n ¼ 131) was 11.6+3.4 years and 79 (60.3%) were female
titative variables were expressed as mean + standard deviation. In (Table 1). Average age of celiac disease diagnosis was
addition, 95% confidence intervals (CIs) were calculated for the head- 7.4+4.0 years old, and the study participants reported to be
ache frequencies. Possible factors contributing to the samples with and on a gluten-free diet for 4.3+3.6 years.
without headaches were analyzed with two-sided P values at a .05 A total of 51 (38.9%) participants had recurrent headaches
significance level. defined as at least 1 episode per month for at least 1 year (95%
Hom et al 39

CI: 31%-47%). Thirty-three had migraine (25%, 95% CI: 18%- Table 2. Factor Analysis via the Presence of Headache.
33%) and 28 had recurrent tension-type headache (22%, 95%
No
CI: 15%-29%). headaches Headaches
Fifty-three participants (40.5%) had an immediate family (n ¼ 80) (n ¼ 51)
history of celiac disease, whereas 88 (67.2%) study participants P
had a family history of headache. Of the 88 participants with a Factor n Statisticsa n Statisticsa value
family history of headache, 65 (73.86%) had a family history of Age when data collected, y 80 11.2 + 3.5 51 12.3 + 3.1 .078b
migraine, 21 (23.86%) had a family history of tension-type Gender 80 51 .78c
headache, and 4 (4.54%) had a family history of headaches that Female 49 (61.3) 30 (58.8)
could not be classified. Headaches appear more common in Male 31 (38.8) 21 (41.2)
patients who have a family history of celiac disease (55% vs Age of CD onset, y 75 5.1 + 3.9 48 5.9 + 4.3 .26b
31%, P ¼ .007) and in patients with a family history of head- Age of CD diagnosis, y 80 6.7 + 4.0 51 8.5 + 3.6 .013b
aches (80% vs 59%, P ¼ .010) (Table 2). Celiac disease Time on gluten-free diet, y 80 4.5 + 3.6 51 4.0 + 3.6 .41b
Compliance to gluten-free 80 51 .20d
patients with headaches were older at the age of celiac disease diet
diagnosis than were celiac disease patients without headache Strict 75 (93.8) 44 (86.3)
(8.5 vs 6.7, P ¼ .013), although age of onset of celiac disease Moderate 5 (6.3) 6 (11.8)
symptoms did not differ (5.9 vs 5.1, P ¼ .26). Loosely 0 (0.0) 1 (2.0)
Patients who had headaches before their celiac disease diag- CD in family 80 25 (31.3) 51 28 (54.9) .007c
nosis were asked about change in their headaches after adopt- HA in family 80 47 (58.8) 51 41 (80.4) .010c
ing a gluten-free diet. Of those participants (n ¼ 32), 22 Type of HA seen in family 43 41 .88d
Migraine 33 (76.7) 28 (73.2)
(68.75%) reported an improvement of their headache sympto- Tension type 7 (16.3) 7 (17.1)
mology after being on a gluten-free diet (Table 3). Nine Migraine þ chronic 1 (2.3) 3 (7.3)
(28.12%) of these patients experienced improvements in head- tension type
ache frequency and thirteen (40.62%) of these patients experi- Cluster HA 1 (2.3) 1 (2.4)
enced improvements in headache frequency and intensity. Migraine þ cluster HA 1 (2.3) 0 (0.0)
Nineteen (59.4%) reported acute medication use of ibuprofen Learning disorder history 80 3 (3.8) 51 5 (9.8) .26d
and seven (21.9%) acetaminophen. Two patients reported use Attention-deficit disorder 80 5 (6.3) 51 7 (13.7) .15c
history
of sumatriptan. Twenty-eight (87.6%) patients reported taking Balance problems history 80 2 (2.5) 51 2 (3.9) .64d
acute medications for their headaches less than three times per Felt weakness history 80 5 (6.3) 51 7 (13.7) .15c
week and four (12.4%) patients reported taking acute medica- Seizures currently 80 0 (0.0) 51 0 (0.0)
tions 3 times or more per week, suggesting the possibility of Seizures past 80 2 (2.5) 51 0 (0.0) .52d
rebound headache for these participants. Seizures with fever 80 1 (1.3) 51 0 (0.0) .99d
Developmental disorder 80 1 (1.3) 51 1 (2.0) .99d
history
Discussion Grades in past year 80 51 .49d
A-B 74 (92.5) 44 (86.3)
Our study identifies a high occurrence of recurrent headache B-C 3 (3.8) 4 (7.8)
and migraine headaches in the pediatric celiac disease popula- C-D 3 (3.8) 3 (5.9)
tion and indicates that a large number of patients with celiac Days of school missed 80 51 .53c
disease who had recurrent headaches experienced improve- 0-5 56 (70.0) 33 (64.7)
ment in their symptoms after being on a gluten-free diet. 5-10 16 (20.0) 11 (21.6)
A literature review from 1990-2018 demonstrates that 10-15 2 (2.5) 4 (7.8)
>15 6 (7.5) 3 (5.9)
headaches in pediatric patients with celiac disease have been
understudied. According to Lionetti et al,13 24.8% of pediatric Abbreviations: CD, celiac disease: HA, headache.
a
patients (ages 3-16 years) with celiac disease have problems Statistics presented as mean + SD or n (column %).
b
Analysis of variance.
with headaches compared to 8% of patients without celiac c
Pearson chi-square test.
disease in their study of 354 celiac disease patients and 200 d
Fisher exact test.
controls. A meta-analysis by Zis and colleagues14 estimated
that the mean pooled prevalence of headache in the pediatric
celiac disease population was 18.3%. Our study cohort of prevalence reported among the general pediatric population.
pediatric celiac disease patients has a higher primary head- Reported prevalence of tension-type headaches, however, in
ache frequency compared to the few studies present in the pediatric population is highly variable (29%-71%), thereby
literature. making the comparison to our frequency data difficult.15,16
Our study results indicate that tension-type frequencies in This study suggests that headaches within the celiac disease
pediatric celiac disease are not higher than those of the general population are more common based on family history of head-
population. The tension-type frequency in our sample (22%, ache, age of celiac disease diagnosis, and family history of
95% CI: 15%-29%) is within the range of tension type celiac disease. In terms of family history, one limitation of this
40 Journal of Child Neurology 35(1)

Table 3. Headache Lifestyle Factors and Gluten-Free Diet Effect on other celiac disease symptoms in children with migraine who
Headaches (n ¼ 32). have not experienced improved symptomology with routine
Factor n Statisticsa
migraine treatment approaches.
A number of limitations must be acknowledged for this
Age of onset of headaches, y 32 7.3 + 3.6 study. First, the frequencies reported are only those of a single
Time since onset of headaches, y 32 4.7 + 3.1 institution and may vary at other institutions or the entire
Acute medications taken 32 celiac disease population. Second, we acknowledge the pos-
Does not take acute medication 6 (18.8)
sibility of selection and response bias as the recruitment pro-
Acetaminophen 7 (21.9)
Ibuprofen 19 (59.4) cess may favor people who perceive headaches. Furthermore,
Acute medicine times taken 32 there is a subjective nature of classifying headaches and the
Less than 3 times per week 28 (87.6) subjectivity of study participant recall. Lastly, the study size
3 times or more per week 4 (12.4) may be limited by a number of factors such as the patients
Current state of HA 32 who had headache shortly before their celiac disease diagno-
Still occur 25 (78.1) sis, limiting the ability to characterize recurrent headache if a
Do not occur 7 (21.9)
gluten-free diet reduced their headache frequency to less than
GFD effect on HA 32
Better (frequency) 9 (28.1) 1 headache per month for 1 year.
Better (frequency and intensity) 13 (40.6) Our study demonstrates that recurrent headaches, most com-
Worse 1 (3.1) monly migraine, are experienced by many pediatric celiac dis-
About the same 9 (28.1) ease patients and that many patients experience improved
symptomology with a gluten-free diet. A larger prospective
Abbreviations: GFD, gluten-free diet; HA, headache.
a
Statistics presented as mean + SD, or n (column %). study of headache in children and adolescents with newly diag-
nosed celiac disease would help to further characterize primary
headache frequency in these children and the impact of gluten-
study is that it cannot be determined if a family history of celiac
free diet adoption on headache symptomology.
disease directly impacts primary headache. We do not rule out
the possibility that the genetics of migraine and celiac disease
are linked, but we are unaware of any literature examining this Acknowledgment
topic. Further work is needed to elucidate any association We thank Matt Karafa of the Cleveland Clinic Department of Quanti-
between migraine and celiac disease–contributing genes. tative Health Sciences for statistical support.
A mechanism linking celiac disease and headache has not
been well elucidated. However, the leading hypothesis pro- Author Contributions
poses that an increased number of proinflammatory cytokines AR and BK were involved in study conception. All authors were
due to an altered inflammatory response contributes to head- involved in the study design. GH and BH collected study data. GH
ache.11 Increased headache frequencies have been reported in wrote the manuscript with all authors contributing to the final manu-
other autoimmune disorders such as Type 1 diabetes, Sjogren script version.
syndrome, Churg-Strauss syndrome, Takayasu arteritis, and
Cogan syndrome. 17,18 In these disorders, the immune Declaration of Conflicting Interests
response likely contributes to increased frequency and sever- The authors declared no potential conflicts of interest with respect to
ity of migraines. the research, authorship, and/or publication of this article.
Many studies indicate positive headache response rates to
gluten-free diet ranging from 69.2%19 to 100%.9,20,21 Our study
Funding
addresses this question through asking participants who had
headaches prior to their celiac disease diagnosis about their The authors received no financial support for the research, authorship,
and/or publication of this article.
headache quality before and after adopting a gluten-free diet.
Our study findings indicate that more than two-thirds of parti-
cipants found their headache quality to be improved in fre- ORCID iD
quency or having both improved frequency and intensity. Grant L. Hom, BA https://orcid.org/0000-0002-1047-7609
These results agree with improved headache symptomology
of previous studies in adults and children and indicate that
Supplemental Material
gluten-free diet can improve headache quality in children and
Supplemental material for this article is available online.
adults.9,11,13,20,21 However, our study indicates that sympto-
mology improvement is on the lower end of previously
reported percentages. Thus, there are likely to be limitations Ethical Approval
in terms of a gluten-free diet’s capacity to improve headaches This study adheres to the Declaration of Helsinki and all human
in pediatric celiac disease patients. These results in addition to research subject guidelines. This study was approved by the Cleveland
those from other studies lend merit for clinicians to ask about Clinic Instutional Review Board (IRB #14-746).
Hom et al
References
1. Gujral N, Freeman HJ, Thomson ABR. Celiac disease: preva-
lence, diagnosis, pathogenesis and treatment. World J Gastroen-
terol. 2012;18(42):6036-6059.
2. Zelnik N, Pacht A, Obeid R, Lerner A. Range of neurologic dis-
orders in patients with celiac disease. Pediatrics. 2004;113(6):
1672-1676.
3. Bushara KO. Neurologic presentation of celiac disease. Gastro-
enterology. 2005;128(4):S92-S97.
4. Lebwohl B, Roy A, Alaedini A, Green PHR, Ludvigsson JF. Risk
of headache-related healthcare visits in patients with celiac dis-
ease: a population-based observational study. Headache. 2016;
56(5):849-858.
5. Sansotta N, Amirikian K, Guandalini S, Jericho H. Celiac disease
symptom resolution. J Pediatr Gastroenterol Nutr. 2018;66(1):
48-52.
6. Cicarelli G, Della Rocca G, Amboni M, et al. Clinical and neu-
rological abnormalities in adult celiac disease. Neurol Sci. 2003;
24(5):311-317.
7. Rashid M, Cranney A, Zarkadas M, et al. Celiac disease: evalua-
tion of the diagnosis and dietary compliance in Canadian children.
Pediatrics. 2005;116(6):e754-e759.
8. Dimitrova AK, Ungaro RC, Lebwohl B, et al. Prevalence of
migraine in patients with celiac disease and inflammatory bowel
disease. Headache J Head Face Pain. 2013;53(2):344-355.
9. Nenna R, Petrarca L, Verdecchia P, et al. Celiac disease in a large
cohort of children and adolescents with recurrent headache: a
retrospective study. Dig Liver Dis. 2016;48(5):495-498.
10. Alehan F, Ozçay F, Eroi I, Canan O, Cemil T. Increased risk for
coeliac disease in paediatric patients with migraine. Cephalalgia.
2008;28(9):945-949.
11. Gabrielli M, Cremonini F, Fiore G, et al. Association between
migraine and celiac disease: results from a preliminary case-
41
control and therapeutic study. Am J Gastroenterol. 2003;98(3):
625-629.
12. Inaloo S, Deghani SM, Farzadi F, Haghighat M, Imanieh MH. A
comparative study of celiac disease in children with migraine
headache and a normal control group. Turkish J Gastroenterol.
2011;22(1):32-35.
13. Lionetti E, Francavilla R, Maiuri L, et al. Headache in pediatric
patients with celiac disease and its prevalence as a diagnostic clue.
J Pediatr Gastroenterol Nutr. 2009;49(2):202-207.
14. Zis P, Julian T, Hadjivassiliou M. Headache associated with coe-
liac disease: a systematic review and meta-analysis. Nutrients.
2018;10(10).
15. Rasmussen B. Epidemiology of headache. Cephalalgia. 2001;
21(7):774-777.
16. Göbel H, Petersen-Braun M, Soyka D. The epidemiology of head-
ache in Germany: a nationwide survey of a representative sample
on the basis of the headache classification of the International
Headache Society. Cephalalgia. 1994;14(2):97-106.
17. John S, Hajj-Ali RA. Headache in autoimmune diseases. Head-
ache J Head Face Pain. 2014;54(3):572-582.
18. Collin P, Kaukinen K, Välimäki M, Salmi J. Endocrinological
disorders and celiac disease. Endocr Rev. 2002;23(4):
464-483.
19. Terrone G, Parente I, Romano A, Auricchio R, Greco L, Del
Giudice E. The Pediatric Symptom Checklist as screening tool
for neurological and psychosocial problems in a paediatric cohort
of patients with coeliac disease. Acta Paediatr. 2013;102(7):
e325-e328.
20. Diaconu G, Burlea M, Grigore I, Anton DT, Trandafir LM. Celiac
disease with neurologic manifestations in children. Rev Med Chir
Soc Med Nat Iasi. 2013;117(1):88-94.
21. Parisi P, Pietropaoli N, Ferretti A, et al. Role of the gluten-free
diet on neurological-EEG findings and sleep disordered breathing
in children with celiac disease. Seizure. 2015;25:181-183.